Background. Endothelial cells produce a number of substances, collectively termed endothelium-derived relaxing factor (EDRF), that promote local relaxation of vascular smooth muscle. Although studies have demonstrated defects in endothelium-dependent vasodilation in animal models of hypertension, atherosclerosis, and heart failure, there are only limited data from human subjects because of the difficulty in obtaining fresh vascular segments.Methods and Results. To address the hypothesis that endothelium-dependent vasodilation is attenuated in patients with heart failure, we measured forearm blood flow responses to the intra-arterial administration of methacholine, a known stimulus of EDRF release through muscarinic receptors. In 14 normal subjects, a dosage range of methacholine increased forearm blood flow by 5.26±+0.63, 10.50±0.63, and 13.22±0.86 ml/min/100 ml forearm volume (FAV); these responses were 1.98+±0.46, 5.48±0.79, and 8.50±+1.53 ml/min/100 ml FAV in 14 patients with heart failure. When pooled over all doses, the responses were strikingly less in the patients with heart failure (5.32+±0.31 versus 9.52+±0.60 ml/min/100 ml FAV; p=0.0003). In a second study, the average difference in forearm blood flow responses between patients with heart failure and normal subjects with methacholine was significantly greater than the average difference between the groups with nitroprusside (4.04±1.10 versus 2.20±0.71 ml/min/100 ml FAV; p=0.04). The decreased methacholine responses in the patients with heart failure were not related to age (r= 0.39; p=NS) or etiology because there was no difference in the responses between patients with ischemic heart disease and those with idiopathic cardiomyopathy.Conclusions. These data suggest that endothelium-dependent vasodilation is attenuated in patients with heart failure. Although the mechanisms of the decreased endothelium-dependent responses in heart failure are not known, this impaired local vasodilation may contribute to characteristic of heart failure. (Circulation

on behalf of the Multicenter InSync ICD II Study GroupBackground-The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated. Methods and Results-The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction Յ35%, a QRS Ն130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak V O 2 , V E/V CO 2 , NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak V O 2 , yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (Pϭ0.04 and Pϭ0.01, respectively), and LV ejection fraction (Pϭ0.02). CRT patients showed statistically significant improvement in V E/V CO 2 (Pϭ0.01), NYHA class (Pϭ0.05), and clinical composite response (Pϭ0.01). No significant differences were noted in 6-minute walk distance or quality of life scores. Conclusions-In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

No abstract